Lithium is the first line of therapy in the treatment of bipolar disorder yet its mechanism of action in this setting is not known. The goal of this project is to apply basic research methods to the study of mental health in order to identify and validate the molecular targets of lithium in the treatment of bipolar disorder. Previous work in this laboratory has shown that lithium inhibits the signaling molecule Glycogen Synthase Kinase-3 (GSK-3) and activates the Wnt/li-catenin signaling pathway, providing an explanation for the effects of lithium on the development of diverse organisms. Several laboratories have also shown that lithium inhibits GSK-3 in cultured neurons and in whole animals;however, GSK-3 has not been validated as the target of lithium that mediates the therapeutic response in bipolar disorder. The ongoing project supported by this RO1 has identified lithium-sensitive behaviors in mice and has shown that mice lacking one copy of the Gsk- 3B gene demonstrate similar behavioral changes, supporting the hypothesis that these behavioral effects of lithium are mediated through inhibition of GSK-3. Similar behavioral changes were also observed in transgenic mice expressing a dominant negative form of GSK-36. This project has also identified a novel regulatory mechanism for GSK-3 that enhances the direct inhibition of GSK-3 mediated by lithium. We have also demonstrated that lithium robustly activates Wnt dependent transcription in limited regions of the brain, including the medial amygdala. Using the pharmacological and genetic tools developed as part of this continuing project, we will further validate GSK-3 as an important target of lithium in the central nervous system. Gsk-3a mutant mice will be examined to evaluate the contribution of GSK-3a to lithium-sensitive behaviors and conditional alleles of Gsk-3a and IS will be generated to disrupt GSK-3 function in a spatially and temporally restricted manner. We will begin to identify the signal transduction pathways downstream of GSK-3 that are responsible for the effects of GSK-3 inhibition. Building on work from the prior funding period, the molecular regulation of GSK-3 activity by components of the Wnt signaling pathway will also be investigated. This approach may allow the development of new and safer therapeutic agents for the treatment of bipolar disorder and should also help to elucidate the neuronal signaling pathways involved in the pathogenesis of this common and debilitating disorder.